Our overall objective is to elucidate the mechanisms that control formation and remodeling of adipose tissues and to determine whether and how these processes are altered by estrogen signaling. Modern life has provided unparalleled access to food supplies, contributing to a worldwide epidemic of obesity and secondary negative health consequences such as diabetes, fatty liver, cardiovascular disease, and even cancer. Thus there is an urgent need to better understand the mechanisms and molecules that control formation of adipocytes and the expansion of adipose tissue. Adipose tissue is highly dynamic, expanding and shrinking in response to various dietary, pharmacologic and hormonal stimuli. For example, estrogen deficiency (e.g., menopause) redistributes fat into metabolically maladaptive visceral fat depots, thereby predisposing or triggering diabetes. In contrast, estrogen shifts deposition into metabolically protective subcutaneous depots, thereby reducing metabolic diseases. Our initial data indicate that remodeling involves both hypertrophy and hyperplasia (stem cell recruitment). That new adipocytes form throughout life indicates the presence of a putative adipogenic stem cell. We recently identified such an adipose stem cell by designing, engineering, and studying mice that express molecular reporters in the adipose lineage. These unique reagents, termed Adipo-Trak, enable us to visualize adipose stem cells in vivo, as well as to follow their descendents as they divide, migrate and develop into mature adipocytes; thereby allowing us to assess estrogen-dependent remodeling. Health risks due to increased adiposity vary depending on adipose tissue deposition; intra-abdominal (visceral) adipose tissue (increased with menopause) carries a much greater risk for cardiovascular disease, diabetes, cancers, and other disorders, than does subcutaneous adipose tissue (induced by estrogen). The focus of this proposal is to delineate how estrogen remodels adipose tissue in this medically relevant manner. By integrating surgical (ovariectomy), pharmacological (estrogen), and genetic (adipose lineage specific estrogen receptor knockouts) manipulations, we will model these morphogenic transformations and determine how they affect adipose lineage specification using our newly developed Adipo-Trak mice. We will define the mechanistic underpinnings of the estrogenic- remodeling effects on adipose stem cells, adipose niche cells and adipocytes. We will also elucidate how physiological and pharmacological stimuli regulate the stem population and the growth of adipose tissue. These studies are designed to elucidate new aspects of adipose biology and metabolic control and how estrogen provides a protective effect, thereby highlighting those that are particularly relevant to new therapies for obesity and diabetes. PUBLIC HEALTH RELEVANCE: The ability to regulate fat storage and metabolism are fundamental processes. However, the dual epidemics of obesity and diabetes endanger millions and are altering our health care landscape. This crisis that could be addressed by identifying genes that control formation, expansion, and remodeling of adipose tissue-for example that regulated by estrogen. We recently identified the adipose stem cell and found that it is important in the normal maintenance of adipose tissue mass and the response to diabetes treatments. Further, adipose lineage cells appear critical for the medically relevant adipose remodeling induced by estrogen or estrogen-deficiency. Our goal is to unravel the developmental, physiological and molecular mechanisms underlying these effects, which we believe will enhance our understanding of adipocyte biology and may lead to novel therapeutic targets for obesity and diabetes.